The goal of this STTR is to provide a preclinically-validated monoclonal antibody or antibody combination for the prevention of respiratory syncytial virus (RSV) in high risk patients including infants and the elderly. Worldwide, 90% of children are infected with RSV before the age of 2, resulting in an estimated 33.8 million lower respiratory tract infections. In the United States adults over 65 have 2.4 million RSV infections causing 203,600 hospitalizations and over 14,000 deaths. Despite the immense impact of RSV on these high risk populations, we lack effective preventative modalities. Recent technological advances in monoclonal antibody discovery and manufacturing have led to increased interest in using monoclonal antibodies as prophylactics for infectious diseases. In collaboration with the Crowe lab at Vanderbilt University Medical Center, we have identified several monoclonal antibodies that have high potential to outperform the current standard of care and expand preventative options to other populations with unmet needs. In this Phase I STTR, we seek to identify promising antibody combinations, evaluate in vivo efficacy, and optimize the manufacturability of our lead anti-RSV monoclonal antibody candidate, so that we can continue to advance preclinical development in Phase II. To accomplish this, we propose the following Aims: Aim 1. Identify the optimal combination of human RSV mAbs for protection. Broad clinical introduction of a preventative antibody carries risk of emergence of resistant RSV viruses. To address this potential problem, we will assess binding and functional performance of diverse anti-RSV antibody combinations for prevention of escape mutations and for synergistic neutralization, followed by selection of the 3-5 highest performing antibody combinations. Aim 2. Determine in vivo efficacy of anti-RSV mAb candidates and select lead. We will place the 3-5 anti-RSV antibodies or combinations in cotton rats to assess in vivo efficacy. Based on in vitro and cotton rat studies, we will select a single or combination lead candidate. Aim 3. Assess manufacturing computational liability and identify candidate siblings with optimized performance and manufacturing computational liability. We have an in silico tool for assessment of manufacturing computational liabilities of the lead candidate. We have unique analytic capabilities and access to the data from the Human Immunome Project (HIP). Using the HIP data and the in silico assessment tool we can identify naturally occurring siblings with superior manufacturability profiles than our original anti-RSV mAb candidates. We will then perform high-throughput binding and neutralization assays to assess performance followed by selection of the optimized lead antibody product. At the end of this Phase I STTR, we will have selected a single optimized lead anti-RSV antibody or combination. We will be poised to launch Phase II, in which we will pursue preclinical development of this lead with the ultimate goal of developing a product that fulfills the unmet need of preventing RSV in high risk patients.